Since Ramon y Cajal proposed that the brain is not a single reticular unit but contains discrete and independent brain cells, neuroscientists have struggled to elucidate the functional properties of distinct brain cell types. This cellular heterogeneity, which arises from cell-type-specific gene expression programs, probably underlies the selective vulnerability of neuronal populations to neurodegenerative disorders. However, the lack of effective tools for molecular profiling and manipulation of specific cell types has hampered progress in identifying disease mechanisms of vulnerable cell populations and developing cell-type specific therapies. As new technology platforms are developed to profile specific cell types in the nervous system, including BacTRAP and single-cell RNA-seq, and genetic tools to manipulate genes or activity in specific neuronal populations, including cre-dependent and channelrhodopsin systems, new opportunities are emerging to experimentally address cell-type heterogeneity and selective vulnerability in vivo. We will take advantage of the latest technologies to identify molecular alterations in inhibitory interneurons associated with cognitive impairment in mouse models of Alzheimer's disease (AD) and humans with AD. We will particularly focus on inhibitory interneurons since they may critically contribute to early brain network alterations (e.g., hyperactivity and deactivation deficits), amyloid-? (A?) deposition, and cognitive alterations in humans with AD and related models. Here, we propose to identify cognitive-relevant molecular alterations in interneuron cell types in two mouse models of AD, J20 and APP-KI mice, by transcriptome profiling using BacTRAP and single-cell RNA-seq, validate our findings in human AD samples, and perform mechanistic studies in mouse models to determine the functional and therapeutic relevance of the identified molecular alterations. Specifically, Aim 1 will determine the RNA-seq transcriptome profile of genetically defined endogenous and transplanted inhibitory cell types (Mafb- and Dlx1-BacTRAP cells) and bulk RNA-seq transcriptome of the cortex and hippocampus of behaviorally characterized NTG, J20, and APP-KI mice. Aim 2 will determine the single-cell RNA-seq transcriptome profile of the full diversity of interneuron sub-types in J20 and APP-KI mice (Aim 2a) and validate it in human samples of AD (Aim 2b). Aim 3 will functionally validate the identified molecular/pathway alterations in J20 mice by modulating their expression levels by cre-dependent deletions or overexpression to determine their causal contribution to brain network and cognition dysfunction in J20 mice. Consistent with our preliminary results, we predict that interneurons have cell-type-specific vulnerability to AD-induced changes and some of those alterations are causally linked to cognitive decline in J20 mice. we predict this research will generate major scientific contributions that will help us to understand network abnormalities and interneuron dysfunction in AD.